1. Technical Field
The present invention relates to triazole compounds and pharmacologically acceptable salts thereof, which have excellent characteristics in terms of pharmacokinetics and antifungal activity, as medicaments (compositions which include carriers) (especially for injection), and to medicaments (especially antifungals) containing said compounds or salts thereof as an active ingredient. The present invention also concerns methods of treating or preventing fungal infections in warm-blooded animals by administering to such animals the triazole compound.
2. Background Art
Various types of triazole compounds have so far been reported as agents for the treatment of fungal infections. For example, triazole compounds having a tertiary hydroxy group are described in Japanese Patent Application Publication No. Hei 8-333350, Japanese Patent Application Publication No. Hei 11-80135, Japanese Patent Application Publication No. Hei 10-279567, and Japanese Patent Application Publication No. 2001-342187. In Japanese Patent Application Publication No. Sho 62-12766, 2-(2,4-difluorophenyl)-1,3bis(1H-1,2,4-triazol-1-yl)-2-propanol (fluconazole) is described. In Japanese Patent Application Publication No. Hei 8-53426, 3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1(1H-1,2,4-triazol-1-yl)-2butanol (ravuconazole) is described. In WO 99/45008, 2-(2,5-difluorophenyl)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (R00094815) is described. In Japanese Patent No. 2625584, 2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (voriconazole) is described. In Japanese Patent Application Publication No. Hei 9-183769, 1-[(1R,2R)-2-(2,4difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (TAK-456) is described. In Japanese Patent Application Publication No. Hei 11-240871, 2-(2,4-difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (SS750) is described. In WO 98/31675, (2R,3R)-2-(2,4-difluorophenyl)-3-[4-[4-[3-oxo-2-(4-trifluoromethoxybenzyl)-2H-1,2,4-triazol-4-yl]phenyl]-1-piperazinyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (Syn-2869) is described. In WO97/05130, 7-chloro-3-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one (UR-9825) is described. Analogous triazole compounds are also described in Japanese Patent No. 3050982, WO 95/25107, WO 00/27852, WO 01/66551, and WO 01/79196.
Further, ester compounds interrupted by a methylenedioxy group for improving the water solubility of agents for the treatment of fungal infections are described in WO 00/30655, WO 99/61017 and WO 01/52852.
The administration form of agents for treatment of fungal infections depends on the kind of the target fungus and the type of infection. As the administration form, there are, for example, oral administration and injection administration. As these administration methods have advantages and disadvantages, both methods of administration are required for a preferable agent for the treatment of fungal infection. Although the triazole agents for the treatment of fungal infection indicated above have excellent antifungal activity, they also have the disadvantage of difficulty in administration by injection because of their low solubility in water.
In order to improve the low solubility in water, the conversion of the hydroxy group into an ester group for increasing the water solubility may be considered. However, as the hydroxy group which these therapeutic agents have in common is a tertiary hydroxy group, there is the disadvantage that the said ester group is not cleaved promptly in vivo after administration owing to its low reactivity, and consequently that the active substance is not released efficiently. Ester compounds interrupted by a methylenedioxy group generate formaldehyde upon cleavage of the ester.
The problem to be resolved by the present invention is to afford triazole compounds esterified on the tertiary hydroxy group which have high solubility in water, can be cleaved in vivo promptly, and are safe compounds because no formaldehyde is generated upon cleavage. Triazole compounds having an ester group on the tertiary hydroxy group relating to the present invention have not been known so far.